There is a clinical need for biocompatible and biodegradable structural matrices that facilitate tissue infiltration to repair/regenerate diseased or damaged tissue. Previous attempts have used a number of naturally occurring, as well as synthetic biodegradable materials as scaffolds in the tissue repair process.
One class of biodegradable and biocompatible materials is the family of polysaccharides. One particular polysaccharide used for scaffolds is hyaluronic acid (HA). HA is a naturally-occurring linear polysaccharide comprised of D-glucuronic acid and N-acetyl-D-glucosamine. The polyanionic polymer has a range of molecular weight of from 1,000-10,000,000 Daltons. The use of purified HA has become common practice for treatments such as corneal transplantation, viscosupplementation of the knee, anti-adhesive barriers in spinal surgeries and wound healing applications.
HA has been explored as a scaffold to enhance the repair of tissue. However, the poor physical properties of natural HA and its rapid resorption by the body has restricted its use to applications where a structurally sound scaffold is not required.
Numerous groups have attempted to modify HA to obtain a more robust and water insoluble biopolymer for tissue engineering applications. One line of modifications involved the use of cross-linking agents. These cross-linking agents include formaldehyde, glutaraldehyde, vinyl sulphone, biscarbodiimides, poly-functional epoxides, glycidyl ether, photocurable cinnamic acid derivatives and adipic dihydrazide. However, they are concerns regarding the potential toxicity of some of the cross-linking agents.
Alternatively, HA derivatives have been obtained by targeting specific functional groups of HA, such as carboxyl, hydroxyl and N-acetyl groups through chemical reactions, such as esterification, acylation, amidation, and sulphation. An example of an esterified-HA is a product sold under the tradename HYAFF 11 (Fidia Advanced Biopolymers, Abano Terme, Italy), which has all of its carboxyl groups esterified with benzyl esters. This material is stable in aqueous media for a few weeks, but completely degrades within 2 months.
In many tissue repair applications, e.g. musculoskeletal tissue repair and/or regeneration, the scaffold must be structurally intact for periods far longer than two months. While the use of HA in tissue repair is desired due to HA's function in extracellular matrices and its recognition by certain cell receptors that regulate attachment, proliferation, differentiation and matrix synthesis of certain cell types, thus far approaches using natural HA or known modified-HA have proven inadequate to provide tissue scaffolds that maintain the structural integrity for extended periods of time that is necessary in applications such as musculoskeletal tissue repair or regeneration. The inventions described herein provide a solution to the need for such tissue scaffolds.